This is a New Investigator proposal to study the cellular and molecular profile of the hippocampus in schizophrenia (SZ) and bipolar disorder (BD). Decreased volume of the hippocampus is one of the most consistent findings of postmortem and structural neuroimaging studies of SZ. There is emerging evidence from neuroimaging studies that the hippocampus is also smaller in BD patients, but this has not been studied yet in postmortem specimens. The cellular basis of hippocampal volume change in psychosis remains poorly understood, but it appears likely that cellular changes affect distinctsubpopulations of interneurons and that molecular changes involve genes related to GABAergic and glutamatergic neurotransmission. The applicant is proposing to study, in the same specimens, three aspects of hippocampal pathology in SZ and BD: cell number, protein expression, and gene expression. Using this integrated approach the applicant will test the hypothesis that decreased hippocampal volume in SZ and BD is regionally selective and that cellular changes are affecting subpopulations of intemeurons differentially. First, whole hippocampus preparations and stereological methods will be used to determine hippocampal volume and the total number of hippocampal neurons. We hypothesize that hippocampal changes in SZ and BD are not widespread and diffuse but selective for interneurons in the anterior region and in sectors CA2-4. Furthermore, we hypothesize that SZ is characterized by selective changes in the cell-poor layers of the hippocampus, i.e. stratum oriens and stratum radiatum/lacunosum/moleculare. Second, stereological methods and immunocytochemical markers will be employed to determine the total number of subsets of hippocampal interneurons. We hypothesize that the total number of parvalbumin-positive hippocampal interneurons will be decreased in SZ, whereas the total number of somatostatin-positive interneurons will be changed in BD. Third, in-situ hybridization experiments will test the hypothesis of a selective decrease of genes expressed in hippocampal interneurons. We hypothesize that the expression of glutamic acid decarboxylase (GAD) mRNA will be decreased in BD and that the expression of the mRNA coding for the NMDA receptor subunit 2C, localized preferentially in interneurons of the human hippocampus, is decreased in SZ. The proposed studies are designed to better understand hippocampal pathology in SZ and BD. A regionally specific volume change together with a selective dysfunction of interneurons could provide the structural basis for a role of the hippocampus inthe cognitive deficits and clinical symptoms seen in patients with SZ and BD.